Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones. (1st January 2021)

• Record Type: Journal Article
• Authors: Elzahhar, Perihan A.; Alaaeddine, Rana A.; Nassra, Rasha; Ismail, Azza; Labib, Hala F.; Temraz, Mohamed G.; Belal, Ahmed S. F.; El-Yazbi, Ahmed F.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 669
• Page End: 684
• Publication Date: 2021-01-01
• Subjects: Pyrazolyl thiazolones -- anti-inflammatory -- cyclooxygenase-1/cyclooxygenase-2 -- 15-lipoxygenase -- macrophage apoptosis; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1887169
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: The work reported herein describes the synthesis of a new series of anti-inflammatory pyrazolyl thiazolones. In addition to COX-2/15-LOX inhibition, these hybrids exerted their anti-inflammatory actions through novel mechanisms. The most active compounds possessed COX-2 inhibitory activities comparable to celecoxib (IC50 values of 0.09–0.14 µM) with significant 15-LOX inhibitory activities (IC50 s 1.96 to 3.52 µM). Upon investigation of their in vivo anti-inflammatory activities and ulcerogenic profiles, these compounds showed activity patterns equivalent or more superior to diclofenac and/or celecoxib. Intriguingly, the most active compounds were more effective than diclofenac in suppressing monocyte-to-macrophage differentiation and inflammatory cytokine production by activated macrophages, as well as their ability to induce macrophage apoptosis. The latter finding potentially adds a new dimension to the previously reported anti-inflammatory mechanisms of similar compounds. These compounds were effectively docked into COX-2 and 15-LOX active sites. Also, in silico predictions confirmed the appropriateness of these compounds as drug-like candidates.